Ceruloplasmin contains the majority of the copper in plasma or serum in humans and animals. Ceruloplasmin levels are markedly increased in pregnancy and cancer, with smaller increases occurring in some other disease states. We have demonstrated that this glycoprotein is the main source of copper for most normal and malignant cells. Turnover of ceruloplasmin copper is rapid, especially in rats with implanted tumors, and substantial amounts of copper accumulate in tumors. Since certain forms of copper chelates are known to inhibit tumor growth, the question arises whether ceruloplasmin or the other forms of serum copper play a role in host defense or, conversely, promote cell proliferation. Since the renewal of this grant, we have made two important additional discoveries about copper components in mammalian serum. First, we have found an additional copper transport protein that appears to function, with albumin, in the transport of dietary copper from the intestine to the liver, where it is incorporated into ceruloplasmin (reappearing in the plasma for further distribution). Second, we have established that, contrary to dogma established in the '50s (using flame atomic absorption and low specific activity copper radioisotopes), ceruloplasmin comprises not 90 to 95% but only about 60% of the total copper in plasma, with substantial additional quantities in albumin and the new copper transport protein fraction (about 15% each) and another 10% or so in components of low molecular weight. The present work is focusing on the purification and characterization of the new copper transport protein of rat and human serum, tentatively named "transcuprein," and on the mechanisms by which ceruloplasmin copper is taken up by cells. With regard to the latter, we are working on the hypothesis that mammalian cells have surface receptors for ceruloplasmin that allow specific binding of ceruloplasmin and transfer of its copper to the cell, either by internalization or by surface transfer. (J)